Evo312: An Evodiamine Analog and Novel PKCβI Inhibitor with Potent Antitumor Activity in Gemcitabine-Resistant Pancreatic Cancer

As an obstinate cancer pancreatic cancer (PC) poses a major challenge due to limited treatment options which include resection surgery, radiation therapy, and gemcitabine-based chemotherapy. In cancer cells, protein kinase C beta I (PKC beta I) participates in diverse cellular processes, including cell proliferation, invasion, and apoptotic pathways. In the present study, we created a scaffold to develop PKC beta I inhibitors using evodiamine-based synthetic molecules. Among the candidate inhibitors, Evo312 exhibited the highest antiproliferative efficacy against PC cells, PANC-1, and acquired gemcitabine-resistant PC cells, PANC-GR. Additionally, Evo312 robustly inhibited PKC beta I activity. Mechanistically, Evo312 effectively suppressed the upregulation of PKC beta I protein expression, leading to the induction of cell cycle arrest and apoptosis in PANC-GR cells. Furthermore, Evo312 exerted an antitumor activity in a PANC-GR cell-implanted xenograft mouse model. These findings position Evo312 as a promising lead compound for overcoming gemcitabine resistance in PC through novel mechanisms.